Urinary bladder cancer accounts for around 2 percent of all neoplasia reported in dogs, and transitional cell carcinoma (TCC), also referred to as invasive urothelial carcinoma (iUC), is the most common type of bladder cancer in dogs (Knapp et al., 2014). Most TCCs are intermediate- to high-grade invasive papillary tumours. Other types of bladder cancer less commonly encountered are squamous cell carcinoma, adenocarcinoma, rhabdomyosarcoma, haemangiosarcoma and lymphoma. Risk factors for the development of TCC include exposure to older generation flea control products and lawn chemicals, obesity, neutered status and breed (Scottish Terriers are predisposed) (Glickman et al., 2004; Raghavan et al., 2004).
Urinary bladder TCCs are most commonly located in the trigonal region of the bladder, although they can be observed in other locations. Common features are papillary lesions and a thickened bladder wall. Approximately 50 percent of dogs will also have urethral involvement and around 30 percent of male dogs also have prostatic involvement. At the time of presentation, around 15 percent of patients may have regional nodal or distant metastasis; the lungs are the most common site of distant metastasis but skeletal bones are also a common predilection site for spread of genitourinary carcinomas (Fulkerson and Knapp, 2015; Charney et al., 2017).
Common clinical signs in dogs with urinary bladder TCC include haematuria, dysuria, pollakiuria and less commonly lameness due to bone metastasis or hypertrophic osteopathy
Common clinical signs in dogs with urinary bladder TCC include haematuria, dysuria, pollakiuria and less commonly lameness due to bone metastasis or hypertrophic osteopathy. These clinical signs are similar to those of lower urinary tract infections and may improve with antibiotic therapy if a secondary infection is present. However, if signs don’t resolve or if they recur soon after cessation of antibiotics, further investigation to rule out a neoplastic aetiology is warranted.
Definitive diagnosis of TCC is made via histopathology, although other diagnostic modalities are often employed first.
Abdominal ultrasound is an important diagnostic tool and is likely to reveal an irregular thickening of the bladder, usually focally, or a distinct papillary mass (Figure 1). A diagnosis of TCC should not be made based on imaging alone, however, as other conditions such as polypoid cystitis can appear very similar.
Urinalysis should also be performed, to include cytology as epithelial cells may be visible on sediment examination. However, differentiating markedly dysplastic/inflammatory epithelium from neoplasia is often challenging and may not be possible on cytology alone. If collecting urine via free catch does not provide a cellular enough sample for cytology, then suction biopsies/traumatic catheterisation can be performed. This involves placement of a urinary catheter (usually with additional fenestrations cut into the tip), the tip of which is then ultrasound-guided to the tumour location. Once in position the catheter is scraped over the surface of the tumour while applying negative pressure to try to harvest a highly cellular urine sample. If there is suspicion of a bladder tumour, then cystocentesis (or percutaneous sampling of the mass) should be avoided as tumour seeding along the needle track can occur; the seeded cells can develop into gross disease rapidly and become very challenging to manage.
Differentiating markedly dysplastic/inflammatory epithelium from neoplasia is often challenging and may not be possible on cytology alone
Alternatively, biopsies can be obtained via cystoscopy or cystotomy. Immunohistochemistry for uroplakin-III may be required following histopathology, to confirm urothelial origin in challenging cases (Knapp et al., 2014).
A useful non-invasive diagnostic test has recently been developed for the diagnosis of canine TCC involving the detection of mutations with the proto-oncogene B-Raf (BRAF). It has been discovered that over 80 percent of canine TCCs harbour mutations in BRAFV595E, with urine detection closely correlated with tumour tissue genotype (Decker et al., 2015; Mochizuki et al., 2015). In the UK, the test is currently available through Laboklin requiring just 5 to 10ml of urine to be submitted. The test is 100 percent specific, meaning a positive result is confirmatory for TCC. However, as approximately 20 percent of TCCs do not demonstrate BRAF mutations, a negative result does not rule TCC out.
Staging for canine bladder TCC should include haematology, biochemistry, urinalysis (as outlined above) and bicavitary imaging. This can include abdominal ultrasound and three-view inflated thoracic radiographs, or thoracic and abdominal CT scan. If possible, CT is superior due to increased sensitivity for the detection of pulmonary metastasis and the ability to screen more widely for bony metastasis. The presence of metastasis is prognostic although should not preclude treatment as most patients will succumb to local disease prior to metastatic disease.
Where possible, surgical resection of gross disease prior to chemotherapy offers prolonged survival compared to chemotherapy alone, although this is often only possible for TCCs in non-trigonal locations. Median survival times (MST) between 498 and 772 days have been reported for dogs undergoing partial cystectomy (Figure 2) followed by adjuvant chemotherapy/medical management (Marvel et al., 2017; Bradbury et al., 2021). Adjuvant medical therapy is always required as local recurrence or multifocal lesions can develop after surgery due to the “field effect”: the concept that there may already be malignant transformation of the entire urothelium in response to carcinogen exposure.
Chemotherapy is the mainstay of TCC management, either alone or following surgery. All chemotherapy should be administered alongside a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), as the majority of TCCs express COX-2 and modest responses can be observed with NSAIDs alone (Lee et al., 2007). It should be noted that chemotherapy is unlikely to achieve a complete response (CR), with most patients only demonstrating partial responses (PR) or stable disease (SD). Despite this, patients can do well with MSTs more than one year reported with chemotherapy alone, with the best results seen in patients that sequentially receive multiple different treatment protocols over the course of their disease. The most commonly used chemotherapy agents are vinblastine, mitoxantrone and carboplatin in combination with NSAIDs; vinblastine alongside an NSAID has emerged as the preferred initial chemotherapy protocol due to higher response rates (58 percent PR) and a good safety profile (Knapp et al., 2016). Often the initial chemotherapy agent is continued for as long as PR or SD is maintained.
When disease progression occurs, the chemotherapy agent should change to the next drug not yet used (eg carboplatin or mitoxantrone) as subsequent responses or SD can be achieved; this process then continues until the tumour is refractory to medical management.
Cyclophosphamide is normally used for the metronomic treatment of cancer but, due to the risk of developing sterile haemorrhagic cystitis (SHC), this is avoided in TCC patients
If maximum tolerated dose injectable chemotherapy is not possible, due to patient or owner factors, then metronomic chemotherapy is a valid alternative. Cyclophosphamide is normally used for the metronomic treatment of cancer but, due to the risk of developing sterile haemorrhagic cystitis (SHC), this is avoided in TCC patients as they may be at higher risk of SHC development and/or the clinical signs of SHC may be difficult to detect as patients are often already demonstrating lower urinary signs due to their disease. Therefore chlorambucil (4mg/m2 once daily), alongside an NSAID, is used instead. A PR is less likely compared to injectable chemotherapy, but SD can still be achieved in around 65 percent of cases (Schrempp et al., 2013).
Any patient receiving medical management should be monitored regularly to assess response to treatment and guide ongoing management decisions. Repeat abdominal ultrasound focusing on the bladder and regional lymph nodes should be performed approximately every six to eight weeks.
Transitional call carcinoma is the most common bladder tumour in dogs and typically occurs as a papillary mass in the trigonal region of the bladder. Diagnosis can be challenging as cytologic confirmation is often difficult; however, urine detection of the BRAF mutation is a simple non-invasive tool that will detect around 80 percent of TCCs. Treatment should involve surgery in amenable cases followed by chemotherapy, or chemotherapy alone. Treatment will not be curative but survival between one and two years can be achieved depending on treatment modalities. Even if surgery or chemotherapy are not elected, palliative therapy with COX-2 selective NSAIDs alone can be beneficial and control the disease and associated clinical signs for many months.